WO2019023459A1 - Dinucléotides cycliques utilisés en tant qu'agents anticancéreux - Google Patents

Dinucléotides cycliques utilisés en tant qu'agents anticancéreux Download PDF

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WO2019023459A1
WO2019023459A1 PCT/US2018/043907 US2018043907W WO2019023459A1 WO 2019023459 A1 WO2019023459 A1 WO 2019023459A1 US 2018043907 W US2018043907 W US 2018043907W WO 2019023459 A1 WO2019023459 A1 WO 2019023459A1
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coor
alkyl
halogen
substituted
taken together
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PCT/US2018/043907
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English (en)
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Brian E. Fink
Dharmpal S. Dodd
Lan-Ying Qin
Zheming Ruan
Yufen Zhao
Lalgudi S. Harikrishnan
Muthoni G. Kamau
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Bristol-Myers Squibb Company
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Priority to EP18752985.4A priority Critical patent/EP3658565B1/fr
Priority to ES18752985T priority patent/ES2932354T3/es
Priority to KR1020207005451A priority patent/KR20200032180A/ko
Priority to JP2020504128A priority patent/JP7186764B2/ja
Priority to CN201880049466.7A priority patent/CN110997691B/zh
Publication of WO2019023459A1 publication Critical patent/WO2019023459A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical

Definitions

  • the invention provides novel compounds, pharmaceutical compositions comprising the compounds, and methods of using them, for example, for the treatment prophylaxis of certain cancers and to their use in therapy.
  • Immunotherapy is a rapidly expanding area of medical treatment in which a patient's immune system is deliberately activated, suppressed or otherwise modulated for a positive therapeutic effect.
  • Immunotherapy agents include such things as cells, antigens, antibodies, nucleic acids, proteins, peptides, naturally occurring ligands and synthetically prepared molecules.
  • Cytokines are small glycoprotein molecules known for their role in causing immune response through complex signaling networks. Cytokines have been explored as immunotherapy agents but their direct administration is hampered by many factors including their short half-life in blood which can only be compensated with frequent and often high doses.
  • One highly promising approach is cytokine induction in which the patient is treated with an immunomodulatory agent that triggers the production of one or more therapeutically beneficial cytokines in their body.
  • STING is an intracellular receptor situated on the endoplasmic reticulum.
  • the binding to STING by an agonist activates a signaling pathway culminating in the induction of Type I IFNs, which are secreted and protect the secreting and nearby cells.
  • STING can be activated by two different pathways, each involving a different type of cyclic dinucleotide ("CDN") agonist.
  • CDN cyclic dinucleotide
  • the agonist is an exogenous CDN used by bacterial pathogens as a second messenger (Burdette et al. 2013).
  • cyclic GMP-AMP synthase detects cytosolic DNA and, in response, synthesizes a CDN that functions as an endogenous STING agonist (Ablasser et al. 2013; Gao et al. 2013; Sun et al. 2013).
  • STING Activation of STING results in up-regulation of IRF3 and NF- ⁇ pathways leading to induction of Interferon- ⁇ and other cytokines. STING is crucial for responses to cytosolic DNA of pathogen or host origin.
  • Two exogenous bacterial STING agonist CDNs are 3'3'-cGAMP and c-GMP.
  • the endogenous STING agonist CDN made by cGAS is 2'3'-cGAMP.
  • the bacterial CDNs are characterized by two 3'5' phosphodiester bridges, while the cGAS-produced CDN is characterized by one 2'5' and one 3'5' phosphodiester bridge.
  • the former CDNs are referred to as 3'3' CDNs and the latter as 2'3' CDNs.
  • 3'3' CDNs also are referred to as the "canonical" form and 2'3' CDNs are referred to as the "non-canonical" form.
  • STING activation has also been reported to be beneficial in the treatment of inflammatory diseases and, in an area of particular current interest, cancer.
  • Administration of a synthetic CDN in combination with the cancer vaccine STINGVAX demonstrated enhanced antitumor efficacy in multiple therapeutic models (Fu et al. 2015).
  • Administration of STING agonists alone has been reported to show potent antitumor immune efficacy in a mouse model (Corrales et al. 2015a).
  • the present invention therefore, provides novel cyclic dinucleotides which may be useful for the treatment of cancer.
  • composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a method of treating cancer which comprises administering to a subject in need thereof a therapeutically effective amount of an activator of STING (of Formula I).
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R 3a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , -S(0)2R al or S(0)2NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH2 or OH;
  • R a is H, CH3, halogen, NH2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH2 or OH;
  • R a is H, CH 3 , halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is O or S
  • R 1 and 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , -S(0)2R al or S(0)2NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 ,
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH2 or OH;
  • R a is H, CH3, halogen, NH2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • Y is CH or N
  • n 0, 1 , 2 or 3;
  • X is O or S
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , -
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is F
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R 3a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , -S(0)2R al or S(0)2NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH2 or OH;
  • R a is H, CH3, halogen, NH2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O or S
  • R 1 and R 2 are each independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -, -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl;
  • R 3 is H, CH 3 , halogen, NH 2 or OH;
  • R a is H, CH 3 , halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is S
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O
  • R 1 and R 2 are each independently
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH 3 , halogen, NH 2 or OH
  • R a is H, CH 3 , halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH3, halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , S(0) 2 R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 3 is H, CH3, halogen, NH 2 or OH;
  • R a is H, CH 3 , halogen, NH 2 or OH; or
  • R 3 and R a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH3, halogen, NH 2 or OH;
  • R 4a is H, CH3, halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al S(0) 2 R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is S
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH3, halogen, NH 2 or OH;
  • R 4a is H, CH3, halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , S(0) 2 R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH 2 or OH;
  • R 4a is H, CH3, halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , -S(0)2R al or S(0)2NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 ,
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH2 or OH;
  • R 4a is H, CH3, halogen, NH2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is O or S
  • R 1 and R 2 are each independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH 3 , halogen, NH 2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is F
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl; Y is CR 5 or N;
  • n 0, 1 , 2 or 3;
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , -S(0)2R al or S(0)2NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl;
  • R 4 is H, CH 3 , halogen, NH 2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is S; X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 ,
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH 2 or OH;
  • R 4a is H, CH3, halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkgyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH 2 or OH;
  • R 4a is H, CH3, halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH 3 , halogen, NH 2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is O or S
  • R 1 and R 2 are each independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH 3 , halogen, NH 2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is S
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b :
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , -S(0)2R al or S(0)2NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 ,
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH2 or OH;
  • R 4a is H, CH3, halogen, NH2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is O
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH 3 , halogen, NH 2 or OH;
  • R 4a is H, CH 3 , halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 4 is H, CH3, halogen, NH 2 or OH;
  • R 4a is H, CH3, halogen, NH 2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , -
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 4 is H, CH3, halogen, NH2 or OH;
  • R 4a is H, CH3, halogen, NH2 or OH; or
  • R 4 and R 4a may be taken together to form a 3-4 membered carbocycle
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0)2R al , -NR al S(0)2NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3;
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl; Y is CR 5 or N;
  • n 0, 1 , 2 or 3;
  • R 2 is The compound according to formula III wherein
  • X is S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH; R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 9 is H, halogen or methyl
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently O
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or C 1-3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR 3 OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR a OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 9 is H, halogen or methyl
  • X 1 , X 2 , X 3 and X 4 are each independently O
  • R 1 and 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 9 is H, halogen or methyl
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is O or S
  • R 1 and R 2 are each independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • R 9 is H, halogen or methyl
  • X is O or S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 ,
  • R al is H or C 1-3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • Y is CR 5 or N
  • n 0, 1, 2 or 3;
  • X is S
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 1 is N or CR a ;
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C: 3-6 cycloalkyl substituted with 0-6 R 5 , CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl
  • R 5 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , - S(0) 2 R al or S(0) 2 NR al R al ;
  • R 5a is H or C 1-3 alkyl
  • R 6 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , - OC(0)R al , -OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , - NR al C(0)NR al R al , -NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al or S(0) 2 NR al R al ;
  • R 8 is H, halogen, C1-3 alkyl, CN, N0 2 , OH, OR al , SR al , -C(0)NR al R al , -COOR al , -
  • Y is CR 5 or N
  • n 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently O or NH;
  • R 1 and R 2 are independently
  • Z 2 is NR b ;
  • R a is H, halogen, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO2, OH, OR al , SR al , -C(0)NR al R al , -COOR al , -OC(0)R al , - OC(0)NR al R al , -NR al R al , -NR al C(0)R al , - NR al COOR al , -NR al C(0)NR al R al , - NR al S(0) 2 R al , -NR al S(0) 2 NR al R al , -S(0)R al , - S(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R b is H, Ci-6 alkyl substituted with 0-6 R 5 , C3-6 cycloalkyl substituted with 0-6 R 5 , -C(0)R al , -C(0)NR al R al , -S(0) 2 R al or S(0) 2 NR al R al ;
  • R al is H or Ci- 3 alkyl

Abstract

La présente invention concerne des composés de formule I, II et III tels représentés ci-dessous (I) (II) (III) dans lesquelles tous les substituants sont définis dans la description, ainsi que des compositions pharmaceutiquement acceptables contenant les composés de l'invention et les dites compositions destinés à être utilisés dans le traitement de divers troubles.
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KR1020207005451A KR20200032180A (ko) 2017-07-28 2018-07-26 항암제로서의 시클릭 디뉴클레오티드
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